Obesity is associated with increased incidence of a number of chronic and progressive diseases including diabetes, cardiovascular disease, cancer, and nonalcoholic steatohepatitis (NASH). With the epidemic of obesity in the U.S., the occurrence of NASH has risen exuberantly, becoming the most common cause of liver disease. The root cause of NASH is likely the chronic oversupply of fatty acids leading to lipid accumulation within the cytosol of hepatocytes (hepatic steatosis). Although hepatic steatosis is extremely prevalent, only a subset of afflicted individuals exhibit NASH, severe liver damage, or progress to cirrhosis. The progressive mechanisms are not entirely clear, but likely involve an inflammatory state including augmented production of reactive oxygen species (ROS) and pro-inflammatory cytokines. This second hit is believed to be required to drive the transition from simple steatosis to steatohepatitis. This application is designed to examine the effects of novel compounds (MSDC-0602 and -0160) on a mouse model of NASH and to tease apart the mechanisms of their action. We have shown in studies conducted in obese rodent models that MSDC compounds improve hepatic and skeletal muscle insulin resistance. Phase 2 clinical trials for these drugs have demonstrated efficacy as a glucose lowering and insulin-sensitizing agents. However, little is known regarding the efficacy of these, and related compounds, for treatment of NASH. We propose to evaluate the effects of MSDC-0602 and -0160 on the development of NASH in rodent models (Aim 1), conduct proof of concept studies to define the mechanistic target and mechanisms of action of MSDC drugs (Aim 2), and to identify novel small molecules with similar modes of action (Aim 3). Successful completion of these studies will provide proof of concept efficacy data to drive clinical trials in human subjects with NASH. Moreover, understanding the mechanism of action of these compounds fully could lead to the identification of new compounds with similar pharmacology and effectiveness as new drug leads to treat this and other chronic metabolic and inflammatory conditions.